US6713652B1 - Process for hydrolyzing optically active amides - Google Patents

Process for hydrolyzing optically active amides Download PDF

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Publication number
US6713652B1
US6713652B1 US09/936,348 US93634801A US6713652B1 US 6713652 B1 US6713652 B1 US 6713652B1 US 93634801 A US93634801 A US 93634801A US 6713652 B1 US6713652 B1 US 6713652B1
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optically active
amides
hydrolysis
amine
amide
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Klaus Ditrich
Wolfgang Ladner
Johann-Peter Melder
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BASF SE
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a novel process for cleaving optically active amides.
  • hydrolytic cleavage of optically active amides having a center of chilarity in the amine moiety of the molecule can be carried out with retention of the center of chirality only under very elaborate conditions or not at all.
  • WO 95/08636 describes an enzymatic process for the resolution of racemates of optically active amines, in which the amines are acylated enantioselectively with an ester, then the acylated amine (amide) and unreacted amine in the mixture are separated and, if required, the optically active amine is liberated from the acylated amine (amide) by amide cleavage.
  • the optically active amine is liberated from the acylated amine (amide) by amide cleavage.
  • no process parameters with which the amide cleavage can be carried out are indicated.
  • WO 97/10201 describes a process for cleaving optically active amides with retention of the center of chirality.
  • the amides are hydrolyzed with alkali metal or alkaline earth metal hydroxide in the presence of a polyol or amino alcohol.
  • the amount of polyol or amino alcohol used is 10-90, preferably 30-80% of the total weight of the mixture.
  • this object is achieved by a process for hydrolyzing optically active amides to carboxylic acids and optically active amines with retention of the center of chirality, where the hydrolysis of the amides is carried out with an alkali metal or alkaline earth metal hydroxide in the presence of 5-30% by weight, based on the amide employed, of a polyol or an amino alcohol.
  • the process according to the invention is suitable for virtually all amides which can be prepared from optically active primary or secondary amines. It is particularly suitable for amides whose amine moiety consists of an optically active arylalkylamines.
  • X is any conventional aromatic substituent, in particular halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylthio.
  • the process according to the invention is also suitable for cleaving amides whose amine moiety consists of an amino alcohol of the formula (I)
  • R 5 , R 6 independently of one another H, branched and unbranched C 1 -C 10 -alkyl, C 1 -C 4 -alkoxycarbonyl, phenyl, phenyl-C 1 -C 4 -alkyl, where the phenyl groups may be substituted by halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylthio. It is also possible for R 5 and R 6 to be connected by a carbon chain which may be interrupted by oxygen, sulfur or nitrogen and in turn may be substituted to form a mono-, bi- or tricyclic system
  • R 7 H, C 1 -C 10 -alkyl, C 1 -C 4 -alkoxycarbonyl
  • R 8 H, C 1 -C 10 -alkyl
  • n 0, 1 or 2, preferably 0 or 1.
  • amino alcohols of the above structure (I) which may be mentioned are:
  • 2-amino-1-butanol 2-amino-1-butanol; ephedrine; pseudoephedrine; norephedrine; norpseudoephedrine; tert-leucinol; phenylglycinol; 1,2-diphenylaminoethanol; cis- and trans-2-aminocyclopentanol; cis- and trans-1-amino-2-hydroxyindan; cis- and trans-2-aminocyclohexanol, statine, 2-hydroxy-3-aminophenylpropionic acid.
  • Preferred amino alcohols which may be mentioned are: cis- and trans-1-amino-2-hydroxyindane.
  • the polyols which can be used in the process according to the invention are glycols, e.g. ethylene glycol and its monoethers e.g. monomethyl glycol.
  • polystyrene resin 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 2,3-butanediol, 2,4-pentanediol, cis- and trans-cyclohexane-1,2-diol, cis- and trans-cyclohexane-1,4-diol, 2-methyl-2,3-butanediol, 3-methyl-2,4-pentanediol, 2,2-dimethyl-1,3-propanediol, 1-phenyl-1,2-ethanediol, 3-methoxy-1,2-propanediol, 3-phenoxy-1,2-propanediol, 3-butene-1,2-diol, cis- and trans-2-butene-1,4-diol, triethanolamine, triisopropanolamine.
  • polyalkylene glycols preferably dialkylene glycols and their ethers, in particular diethylene glycol and diglyme, as polyols.
  • Preferred polyols are ethylene glycol and diethylene glycol.
  • Suitable amino alcohols for the amide cleavage according to the invention are ethanolamine, diethanolamine and triethanolamine.
  • Triethanolamine is the particularly preferred amino alcohol.
  • polyols or amino alcohols should be soluble in water or homogeneously miscible with water. It is also possible to employ mixtures of polyols or amino alcohols.
  • the polyols are used in an amount of 5-30, preferably 5-20 and, particularly preferably 8-15% of the weight of the amide employed.
  • Another necessary component in the cleavage according to the invention is an alkali metal or alkaline earth metal hydroxide, in particular sodium or potassium hydroxide. This catalyzes the hydrolysis but is also neutralized by the acid produced, so that it is normally employed in an amount of 1-10 equivalents based on amide.
  • the hydroxides can advantageously be employed in the form of their aqueous solutions because a certain amount of water is required anyway in the cleavage according to the invention.
  • the amount of water is usually 5-90% of the total weight of solvent.
  • the cleavage according to the invention is preferably carried out at temperatures above 100° C. particularly preferably between 100 and 180° C.
  • the hydrolysis according to the invention of the amides can be carried out either batchwise or continuously.
  • the resulting amine is separated and isolated from the carboxylic acid which is in the form of a salt.
  • This preferably takes place be extraction, employing as extractants ethers such as diethyl ether, methyl tert-butyl ether and dibutyl ether, halogenated hydrocarbons such as dichloromethane or trichloroethylene or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene and xylene.
  • ethers such as diethyl ether, methyl tert-butyl ether and dibutyl ether
  • halogenated hydrocarbons such as dichloromethane or trichloroethylene
  • hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene and xylene.
  • a likewise preferred embodiment of the isolation of the amine is steam distillation.
  • a particularly suitable embodiment of the invention consists of carrying out the cleavage at such a high temperature that the product resulting from the reaction (amine) is distilled out with steam and thus immediately removed from the reaction mixture, whereas the acid, which is in dissociated form under the alkaline conditions, remains where it was.
  • step 3 The process according to the invention can be employed very successfully as one step (step 3) in the process described in WO 95/08636 for resolving racemates of primary and secondary amines.
  • This process comprises the following steps:
  • esters suitable for this process are those in which an electron-rich heteroatom is bonded to a carbon atom in the alpha, beta or gamma position relative to the carbonyl carbon in the acid component of the ester.
  • the heteroatom can be a fluorine, nitrogen, oxygen, phosphorus or sulfur atom. Oxygen is preferred as heteroatom.
  • the heteroatom may optionally be linked to other groups, e.g. alkyl groups. If the heteroatom is, for example, oxygen, an ether group is present.
  • the alcohol component of the ester may consist of branched or unbranched C 1 -C 10 -alcohols, which may also optionally be substituted.
  • Particularly suitable alcohol components are 2-propanol, 2-butanol, 2-pentanol, 3-pentanol, 3-methyl-2-butanol, cyclopentanol, cyclohexanol, 2-methylcyclohexanol, 1-chloro-2-propanol, 1-bromo-2-propanol, 4-methyl-2-pentanol, 2,4-dimethyl-3-pentanol, cyclopropylethanol, 1-phenylethanol, 1-phenoxy-2-propanol, 1-methoxy-2-propanol, cis- and trans-2-methoxycyclohexanol, 1-dimethylamino-2-propanol, 1-buten-3-ol, 1-butyn-3-ol, 1-indanol, 2-indanol, 3-hydroxytetrahydrofuran, 5-hydroxy-2-methyl-1,3-dioxane, 4-hydroxypiperidine, (+) and ( ⁇ )-menthol, (+
  • Suitable alcohol components are 1,2-ethanediol, glycerol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 2,3-butanediol, 2,4-pentanediol, cis- and trans-cyclohexane-1,2-diol, cis- and trans-cyclohexane-1,4-diol, 2-methyl-2,3-butanediol, 3-methyl-2,4-pentanediol, 2,2-dimethyl-1,3-propanediol, 1-phenyl-1,2-ethanediol, 3-methoxy-1,2-propanediol, 3-phenoxy-1,2-propanediol, 3-chloro-1,2-propanediol, 3-bromo-1,2-propanediol, 3-butene-1,2-diol, cis-
  • esters are those of the structure
  • R 1 C 1 -C 10 -alkyl
  • R 2 C 1 -C 10 -alkyl, H,
  • R 3 H, C 1 -C 10 -alkyl, phenyl optionally substituted by NH 2 , OH, C 1 -C 4 -alkoxy or halogen,
  • R 4 H, C 1 -C 10 -alkyl, phenyl optionally substituted by NH 2 , OH, C 1-4 -alkoxy or halogen,
  • n 0, 1 or 2.
  • the C 1 -C 4 -alkyl esters of C 1 -C 4 -alkoxyacetic acids are preferred.
  • the methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and tert-butyl esters of methoxyacetic acid are very particularly preferred.
  • a large number of enzymes can be employed as hydrolases in said process.
  • Proteases and, in particular lipases are preferably used.
  • Particularly suitable lipases are microbial lipases which can be isolated, for example, from yeasts or bacteria.
  • Particularly suitable lipases are those from Pseudomonas, e.g.
  • hydrolases are the enzymes, commercially available from Novo Nordisk (Enzyme Toolbox), in particular the lipases SP 523, SP 524; SP 525, SP 526 and Novozym® 435.
  • the enzyme used can be employed in the native or immobilized form.
  • the immobilized enzyme Novozym® 435 is particularly suitable.
  • Suitable solvents are in general organic solvents.
  • the reaction proceeds particularly well in ethers, for example in MTBE or THF, in hydrocarbons such as hexane, cyclohexane, toluene or halogenated hydrocarbons such as methylene chloride.
  • reaction can also be carried out in the absence of a solvent.
  • reaction proceeds particularly well if the solvents and starting materials are if possible in anhydrous form.
  • the reaction of the ester with the racemic amine or amino alcohol with enzyme catalysis is normally carried out at room temperature.
  • the times for this reaction are from 1 to 48 hours, depending on the substrate and quantity of enzyme.
  • Secondary amines/amino alcohols usually require longer reaction times than do primary amines/amino alcohols.
  • the lower reactivity of secondary amines can also be compensated by increasing the quantity of catalyst relative to primary amines.
  • ester From 1 to 6 mol of ester are preferably added per mole of substrate to be reacted, i.e. from 0.5 to 3 mol of ester are required for 1 mol of racemic amine.
  • the quantity of enzyme to be added depends on the nature of the hydrolase and the activity of the enzyme preparation.
  • the optimal quantity of enzyme for the reaction can easily be determined by simple preliminary tests. As a rule, 1000 units of lipase are added per mmol of amine or amino alcohol.
  • the progress of the reaction can easily be followed by conventional methods, for example by gas chromatography.
  • the enzyme can be retained in a flow-through reactor.
  • the enantioselective reaction of the racemic substrate with the ester results in the corresponding acylated product (amide) from one enantiomer, whereas the other enantiomer remains unchanged.
  • the amine and amide which are then present in the mixture can easily be separated by conventional methods. Extraction or distillation processes are, for example, very suitable for separating the amine and amide in the mixture.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US09/936,348 1999-03-24 2000-03-17 Process for hydrolyzing optically active amides Expired - Lifetime US6713652B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19913256A DE19913256A1 (de) 1999-03-24 1999-03-24 Verfahren zur Hydrolyse von optisch aktiven Amiden
DE19913256 1999-03-24
PCT/EP2000/002380 WO2000056699A1 (de) 1999-03-24 2000-03-17 Verfahren zur hydrolyse von optisch aktiven amiden

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US (1) US6713652B1 (de)
EP (1) EP1163206B1 (de)
JP (1) JP4578688B2 (de)
CN (1) CN1182102C (de)
AT (1) ATE303985T1 (de)
CA (1) CA2367897C (de)
DE (2) DE19913256A1 (de)
DK (1) DK1163206T3 (de)
ES (1) ES2248064T3 (de)
WO (1) WO2000056699A1 (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103012154A (zh) * 2012-12-18 2013-04-03 浙江大学 由苯磺酰胺衍生物氨解制备有机胺的方法
US9115052B2 (en) 2009-01-16 2015-08-25 Basf Se Separation of an enantiomer mixture of (R)- and (S)-3-amino-1-butanol

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10062729A1 (de) * 2000-12-15 2002-06-20 Basf Ag Verfahren zur Racemisierung von optisch aktiven Aminen
DE102006032061B4 (de) * 2006-07-11 2009-01-02 Mark, Christoph, Dr. Verfahren zur Herstellung von optisch aktiven Aminen
CN102154432B (zh) * 2010-12-20 2013-06-12 蚌埠丰原医药科技发展有限公司 一种雷沙吉兰的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008636A1 (de) 1993-09-25 1995-03-30 Basf Aktiengesellschaft Racematspaltung primärer und sekundärer amine durch enzym-katalysierte acylierung
WO1997010201A1 (de) 1995-09-15 1997-03-20 Basf Aktiengesellschaft Spaltung von optisch aktiven amiden

Family Cites Families (1)

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US3592854A (en) * 1968-07-19 1971-07-13 Armour Ind Chem Co Hydrolysis of amides to amines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008636A1 (de) 1993-09-25 1995-03-30 Basf Aktiengesellschaft Racematspaltung primärer und sekundärer amine durch enzym-katalysierte acylierung
WO1997010201A1 (de) 1995-09-15 1997-03-20 Basf Aktiengesellschaft Spaltung von optisch aktiven amiden
US5905167A (en) * 1995-09-15 1999-05-18 Basf Aktiengesellschaft Separation of optically active amides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Devant & Braun, Chem. Berichte 119, 1986 2197-2207.
White, J. Am. Chem. Soc. 77, 1955 6008.

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9115052B2 (en) 2009-01-16 2015-08-25 Basf Se Separation of an enantiomer mixture of (R)- and (S)-3-amino-1-butanol
CN103012154A (zh) * 2012-12-18 2013-04-03 浙江大学 由苯磺酰胺衍生物氨解制备有机胺的方法
CN103012154B (zh) * 2012-12-18 2014-10-08 浙江大学 由苯磺酰胺衍生物氨解制备有机胺的方法

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DK1163206T3 (da) 2005-11-14
JP4578688B2 (ja) 2010-11-10
ES2248064T3 (es) 2006-03-16
ATE303985T1 (de) 2005-09-15
CA2367897C (en) 2009-10-13
EP1163206B1 (de) 2005-09-07
DE19913256A1 (de) 2000-09-28
DE50011119D1 (de) 2005-10-13
EP1163206A1 (de) 2001-12-19
CN1346342A (zh) 2002-04-24
JP2002540093A (ja) 2002-11-26
CN1182102C (zh) 2004-12-29
CA2367897A1 (en) 2000-09-28
WO2000056699A1 (de) 2000-09-28

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